Tuesday, July 1, 2025 7/1/2025

SMARCB1 regulated SWI/SNF complex function in Malignant Rhabdoid Tumors

Award Number: R01CA259850
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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SMARCB1 regulated SWI/SNF complex function in Malignant Rhabdoid Tumors - PROJECT SUMMARY A research program will be undertaken to study SMARCB1-regulated SWI/SNF complex function in malignant rhabdoid tumors. Over the past few years, major cancer genome sequencing studies have identified frequent inactivating mutations of mammalian SWI/SNF chromatin remodeling complex in over 25% of human cancers. Despite the prevalence of SWI/SNF mutations, the contributions of these alterations to tumorigenesis remain unclear. SMARCB1, a core subunit of the complex, was the first subunit linked to cancer when it was found to be recurrently mutated in almost all cases of malignant rhabdoid tumors (RT). While studies using genetically engineered mouse models have firmly established SMARCB1 as a tumor suppressor, the epigenetic mechanism by which SMARCB1 mutation drives tumorigenesis remains elusive. The central hypothesis is that the biochemical diversity of the SWI/SNF complex composition determines its function in proper chromatin targeting to maintain discrete chromatin landscapes and transcriptional programs. Mutation of SMARCB1 leads to aberrant intra- and inter-complex protein-protein interactions that influence chromatin targeting, which consequently alters chromatin landscapes and higher-order structures, and promote an oncogenic epigenome and transcriptome. The objective is to determine the role of SMARCB1 in SWI/SNF subcomplex formation and the impact of these dynamics on chromatin targeting and higher-order chromatin structure. Our ultimate goal is to determine the fundamental epigenetic mechanism(s) by which loss of this chromatin regulatory subunit drives rhabdoid tumor development. To test this hypothesis, we will use a combination of cutting edge biochemical, molecular, and high-throughput sequencing technologies to move forward the program through the following specific aims: Aim 1, Determine SMARCB1 regulated SWI/SNF subcomplex assembly dynamics and identify SWI/SNF interactome in rhabdoid tumors; Aim 2, Determine the chromatin targeting activities of SWI/SNF subcomplexes and their relationship with other epigenetic regulators in rhabdoid tumors; Aim 3, Define higher- order chromatin structures regulated by the SWI/SNF complex in rhabdoid tumors.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $375,150 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Cause and Prevention Research	000	5	3/13/2025	NON-COMPETING CONTINUATION	$337,635
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Cause and Prevention Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$37,515
														Subtotal = $375,150

Issue Date FY: 2024 ( Subtotal = $356,393 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Cause and Prevention Research	001	4	4/22/2024	NON-COMPETING CONTINUATION	$18,758
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Cause and Prevention Research	000	4	3/15/2024	NON-COMPETING CONTINUATION	$337,635
														Subtotal = $356,393

Issue Date FY: 2023 ( Subtotal = $367,647 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Cause and Prevention Research	000	3	3/16/2023	NON-COMPETING CONTINUATION	$367,647
														Subtotal = $367,647

Issue Date FY: 2022 ( Subtotal = $375,150 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Cancer Cause and Prevention Research	000	2	3/7/2022	NON-COMPETING CONTINUATION	$337,635
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Cause and Prevention Research	001	2	5/11/2022	NON-COMPETING CONTINUATION	$37,515
														Subtotal = $375,150

Issue Date FY: 2021 ( Subtotal = $375,150 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Cause and Prevention Research	000	1	3/24/2021	NEW	$375,150
														Subtotal = $375,150

Grand Total All Awards = $1,849,490

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SMARCB1 regulated SWI/SNF complex function in Malignant Rhabdoid Tumors

Award Number: R01CA259850

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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